Interpretive Summary: Altered vitamin D status may play a role in the development of type 2 diabetes. In this study, we examined prospectively the association between vitamin D status, assessed by plasma 25-OHD concentration, and risk of incident type 2 diabetes in a case-control study nested within the Nurses’ Health Study, a large longitudinal observational cohort of women. The final analytical sample consisted of 608 cases of incident type 2 diabetes and 569 controls. Incident cases of type 2 diabetes were identified by self-report and confirmed by a supplementary questionnaire about symptoms, diagnostic laboratory test results, and diabetes treatment. Serum 25-OHD was measured by the DiaSorin radioimmunoassay. In this study of middle-aged women, plasma 25OHD concentrations were inversely associated with development of type 2 diabetes. This association was independent of known diabetes risk factors, including age, body mass index (BMI), and race. Because observational studies of vitamin D have a high potential for confounding, these results need to be confirmed in randomized controlled trials that are specifically designed to test the hypothesis that vitamin D supplementation reduces risk of developing type 2 diabetes among high-risk populations.

Technical Abstract:
Vitamin D may modify risk of type 2 diabetes; however, the association between vitamin D and type 2 diabetes is uncertain. To determine prospectively the association between 25-hydroxyvitamin D (25-OHD) concentration and risk of incident type 2 diabetes, independent of obesity and other known diabetes risk factors. In a nested case-control study conducted among 559 women with newly diagnosed type 2 diabetes and 559 matched controls in the Nurses’ Health Study, we measured the association between baseline plasma 25-OHD and risk of incident diabetes. Controls were frequency matched to cases for age, race and season. Analyses were adjusted for body mass index (BMI) and other risk factors for type 2 diabetes. At baseline, mean 25-OHD was higher in controls vs. cases (23.1 vs. 20.9 ng/ml). After adjusting for matching factors and risk factors without body mass index, higher levels of 25-OHD were associated with a lower risk for type 2 diabetes (the odds ratio for incident diabetes in the top vs. the bottom quartile was 0.54 (95% confidence interval [CI], 0.00, 0.00). Adjustment for BMI attenuated the relationship but remained statistically significant (OR 0.54-no different from above 0.54; 95%CI, 0.00, 0.00). The associations were consistent across subgroups of race and baseline body mass index, age, and calcium intake. The association was stronger among non-whites (OR 0.07; 95%CI 0.01, 0.49) and overweight/obese women (OR 0.46; 95%CI 0.25, 0.83) but the tests for interactions were not statistically significant. Plasma 25-OHD concentration was associated with lower risk of incident type 2 diabetes in women independent of BMI and other known diabetes risk factors. The role of vitamin D in modifying diabetes risk needs to be confirmed in clinical trials.